Traumatic brain injury (TBI) is a dominant cause of death and permanent disability worldwide. Although TBI could significantly increase the proliferation of adult neural stem cells in the hippocampus, the survival and maturation of newborn cells is markedly low. Increasing evidence suggests that the secretome derived from mesenchymal stem cells (MSCs) would be an ideal alternative to MSC transplantation. The successive and microenvironmentally responsive secretion in MSCs may be critical for the functional benefits provided by transplanted MSCs after TBI. Therefore, it is reasonable to hypothesize that the signaling molecules secreted in response to local tissue damage can further facilitate the therapeutic effect of the MSC secretome. To simulate the complex microenvironment in the injured brain well, we used traumatically injured brain tissue extracts to pretreat umbilical cord mesenchymal stem cells (UCMSCs) in vitro and stereotaxically injected the secretome from traumatic injury‐preconditioned UCMSCs into the dentate gyrus of the hippocampus in a rat severe TBI model. The results revealed that compared with the normal secretome, the traumatic injury‐preconditioned secretome could significantly further promote the differentiation, migration, and maturation of newborn cells in the dentate gyrus and ultimately improve cognitive function after TBI. Cytokine antibody array suggested that the increased benefits of secretome administration were attributable to the newly produced proteins and up‐regulated molecules from the MSC secretome preconditioned by a traumatically injured microenvironment. Our study utilized the traumatic injury‐preconditioned secretome to amplify neurogenesis and improve cognitive recovery, suggesting this method may be a novel and safer candidate for nerve repair. Cover Image for this issue: doi:

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